The induction of both CD4+ and CD8+ T cell responses will be of central importance for vaccine protection against HIV-1. However, a number of major questions must be answered before a vaccine can be developed that optimizes these immune responses. While we know that an optimal vaccine-induced antibody response will require CD4+ T cell help, the nature of the help that will potentiate the highest titer and most durable antibody response remains unclear. Although CD8+ T cells have been shown to contribute to containment of HIV-1 replication, the effectiveness of this anti-viral response is limited by the extreme sequence variability of circulating HIV-1 strains and the propensity of the virus to mutate away from recognition by these effector cells. Truly effective CD8+ T cell containment of HIV-1 replication can only occur if T cell responses are generated through vaccination that can pre-empt the ability of the virus to escape from cellular immune recognition. The studies described in this focus address these central issues in HIV-1 vaccine development. Specific Aims are as follows. Aim 1. Evaluate different priming vectors for their ability to stimulate CD4+ Th2 cells and T follicular helper (Tfh) cells in macaques. Aim 2. Characterize CD4+ Th2 cell and Tfh cell responses elicited by HIV-1 vaccines in humans Aim 3. Determine impact of naive repertoires on post-vaccination response of HIV-1 Env-specific CD4+T cells in humans. Aim 4. Compare mosaic and conserved region vaccines for their induction of CD8+ T cell responses. Aim 5. Apply new understanding of immunodominance to improve vaccine-elicited CD8+ T cell responses. The information gained in addressing these aims will lead directly to the design of the next generation of vaccines that will stimulate more protective CD4+ T cell and CD8+ T cell responses.